Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in adults and the aging population. There is no cure for OA. Current treatments, mainly focusing on pain management and improving or sustaining function and have no clearly demonstrated beneficial effect on chondroprotection or OA disease modification. Long-term use of available pharmacological agents to relieve OA symptoms often cause serious adverse events. There is an unmet need for OA disease-modifying therapies which can also relieve pain and be safe for long-term use. Through targeted drug screenings, a combination of generally recognized as safe (GRAS) compounds, designated as C'-CEO, were identified that synergistically induce the expression of a recently identified chondroprotective molecule and suppress inflammation, oxidative stress responses, catabolic activity, the production of pain mediators in vitro. Oral administration of C'-CEO delayed OA onset, reduced OA severity and relieved OA-related pain in destabilization of the medial meniscus (DMM) mice, a model of post-traumatic OA through oral administration in the form of enteric-coated capsules. The proposed study aims to validate these suggested efficacies of C'-CEO in a well-established rat OA model induced by anterior cruciate ligament transection (ACLT). Effects of C'-CEO in mitigating OA disease onset and progression will be carried out in rats subjected to C'-CEO treatment starting the same day of the ACLT surgery, before OA initiation, or starting 4 weeks after surgery, when OA is at a moderate stage. A positive outcome of C'-CEO in preventing or delaying the onset of OA, and in mitigating OA disease progression will be determined by OARSI score (histologic grading of severity of OA) at the end of the experiment. A positive result being a lower score. We also expect C'-CEO treatment will result in reduced cleavage of cartilage extracellular matrix components, increased expression a specific novel target gene, and reduced expression of pro-inflammatory cytokines and proteolytic enzymes. A positive outcome of C'-CEO in relieving OA-related pain symptoms will be determined by testing mechanical sensitivity, weight bearing forces, and expression of pain mediators and sensitizing molecules in the pain pathway. The study also aims to select a suitable ratio of C'-CEO components and a dose for preclinical studies in Phase II. The safety of these compositions will be closely observed. Aiming to develop C'-CEO as a disease- and symptom-modifying drug for treating and preventing OA and is safe for long-term use, the success of the study is expected to establish the scientific merit and technical feasibility for pre-clinical study in Phase II and n human clinical trials.